A primary knowledge of normal mechanisms of immune tolerance, the kind of determinants recognized by tolerant and autoreactive T cells, and the nature of the tolerant and autoreactive lymphocytes themselves, are required before the immunological events leading to autoimmunity may be understood. Much has been learned about immune tolerance to membrane and secreted antigens in recent years, largely through the use of transgenic technology, but here is a gap in knowledge regarding normal mechanisms of tolerance to protein antigens of the nucleus. Yet, the majority of autoantigens, like LaJSS-B, targeted in a number of systemic autoimmune diseases including Sjogren's syndrome and systemic lupus erythematosus are composed of protein and localize to the nucleus. Pathways through which nuclear antigens become visible to the immune system are fundamentally different from previously well-studied membrane and secreted antigens. In order for tolerance and autoimmunity to nuclear antigens to be comprehended, a requirement for unraveling the etiology(ies) of systemic autoimmune disease(s), it is therefore imperative hat nuclear antigens be studied as a special class of antigen. To address these issues, the role of autoreactive T cells in tolerance and autoimmunity to the La systemic nuclear autoantigen will be studied as a paradigm for protein antigens of the nucleus. The studies will utilize a model of T cell initiated anti-nuclear autoimmunity in mice bearing the human La (hLa) transgene in its natural form. Preliminary studies reveal functional T cell tolerance to the hLa neo-antigen in this system. In the current proposal, the La T cell determinant(s) responsible for inducing this observed tolerance will be determined, and the relative roles of T cells recognizing immunodominant and subdominant determinants in tolerance and autoimmunity to the La nuclear antigen will be resolved. It will be determined whether peripheral tolerance to a nuclear antigen occurs and by what potential mechanism(s). Finally, the influence of Type 1 versus Type 2 immunity on tolerance and autoimmunity to the La nuclear antigen will be determined. These studies will advance our collective understanding of anti-nuclear autoimmunity underlying a constellation of systemic autoimmune disorders.